Trial of Dextromethorphan in Rett Syndrome

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Baltimore,
Maryland21205

Purpose:

Increased brain glutamate and its NMDA receptors found in the brain of younger Rett syndrome
(RTT) patients cause toxic damage to neurons (the brain's nerve cells), and contributing to
EEG spikes. Dextromethorphan (DM) acts by blocking NMDA/glutamate receptors. This study is
being done to determine if DM will prevent the harmful over-stimulation of the neurons
thereby reducing EEG spike activity. Treatment with DM consists of one of 3 different doses
(0.25 mg/kg per day; or 2.5 mg/kg/day; or 5mg/kg/day), and aims to find out which dose if
any will help improve EEG abnormalities, behavior, cognition, and reduce seizures, as well
as improve breathing abnormalities, motor capabilities, bone density, and GI dysfunction.
The study will include 90 females and males with RTT, 2 years-14.99 years of age, with a
mutation in the MECP2 gene, and spikes on EEG, with or without clinical seizures.

Study summary:

Patients meeting eligibility criteria(mutation +ve and having EEG spikes), will be admitted
to the Pediatric Clinical Research Unit at Johns Hopkins Hospital and will have
pharmacokinetics of DM determined to establish that they are rapid metabolizers of the drug.
The baseline studies on initial admission include neurological,
neuropsychology,gastroenterology, DEXAscan, Occupational and Physical therapy evaluations,
Brain stem auditory evoked responses and MisMatch negativity testing,gait
analysis,esophageal manometry and pH probe studies. If the subject is a rapid metabolizer
they will be randomized to one of the three drug doses. They are contacted by telephone,
weekly in the first month, and monthly thereafter. They will be examined by a neurologist at
2 weeks,1 month, and 3 months during the drug trial. At each of these visits they will also
be monitored for changes in CBC, electrolytes, and EKG. At the end of the 6 month drug
trial the patients will be readmitted to Johns Hopkins Hospital when all baseline studies
are repeated. Cost of travel, hospitalization and interim tests are free to participants.

Criteria:

Inclusion Criteria:
1. those who have classic or atypical RTT with a proven mutation in the MeCP2 gene;
2. those with documented EEG evidence of spike activity who may or may not have clinical
seizures;
3. subjects must be between 2years -14.99 years of age.
Exclusion Criteria:
1. those without an established mutation in the MeCP2 gene;
2. those who do not have EEG evidence of spike activity;
3. those with mutations in the MeCP2 gene but who have had brain resection or surgical
intervention; for example, tumor, hydrocephalus, severe head trauma; or, an
associated severe medical illnesses such as vasculopathies, malignancies, diabetes,
thyroid dysfunction, etc;
4. those on medications that could interact with DM, e.g. MAO inhibitors, SSRI,
sibutramine etc. to avoid a serotonin syndrome; quinidine and drugs metabolized by
the CYP450 isoform CYP2D6 (e.g. amiodarone, haloperidol, propafenone, thioridazine);
5. those proven to be intermediate or slow metabolizers of DM;
6. those with reported adverse reactions to DM;
7. those whose pregnancy test is positive; and,
8. those showing poor compliance with any aspect of the study;
9. foster children